The present invention relates to novel pyridyl cyanoguanidine prodrugs and their inclusion in pharmaceutical compositions, as well as their use in the manufacture of medicaments.
Pyridyl cyanoguanidines such as pinacidil (N-1,2,2-trimethylpropyl-Nxe2x80x2-cyano-Nxe2x80x3-(4-pyridyl)guanidine) were originally discovered to be potassium channel openers and were consequently developed as antihypertensive agents. Replacement of the side chain of pinacidil by longer aryl-containing side chains caused a loss of the antihypertensive activity, but such compounds were, on the other hand, found to show antitumour activity on oral administration in a rat model carrying Yoshida ascites tumours.
Different classes of pyridyl cyanoguanidines with antiproliferative activity are disclosed in, for instance, EP 660 823, WO 98/54141, WO 98/54143, WO 98/54144, WO 98/54145, WO 00/61559 and WO 00/61561. The structure-activity relationships (SAR) of such compounds are discussed in C. Schou et al., Bioorganic and Medicinal Chemistry Letters 7(24), 1997, pp. 3095-3100, in which the antiproliferative effect of a number of pyridyl cyanoguanidines was tested in vitro on different human lung and breast cancer cell lines as well as on normal human fibroblasts. The compounds were also tested in vivo in nude mice carrying a human lung cancer tumour xenograft. Based on the SAR analysis, a specific compound (N-(6-(4-chlorophenoxy)hexyl)-Nxe2x80x2-cyano-Nxe2x80x3-(4-pyridyl)guanidine) was selected for its high antiproliferative activity in vitro and potent antitumour activity in the nude mouse model.
P-J V Hjarnaa et al., Cancer Res. 59, 1999, pp. 5751-5757, report on the results of further testing of the compound N-(6-(4-chlorophenoxy)hexyl)-Nxe2x80x2-cyano-Nxe2x80x3-(4-pyridyl)guanidine in in vitro and in vivo tests. The compound exhibited a potency in vitro which was comparable to that of the reference cytostatic agents daunorubicin and paclitaxel, while showing considerably less antiproliferative activity on normal human endothelial cells. In in vivo tests using nude mice transplanted with human tumour cells, the compound showed substantial antitumour activity, also against tumour cells that were resistant to conventional anticancer drugs such as paclitaxel.
While, as indicated above, pyridyl cyanoguanidines are promising antitumour agents with an extremely interesting activity profile, they are highly lipophilic and consequently sparingly soluble compounds and are, as such, generally available for oral administration only. However, many cancer patients are in a severely debilitated condition as a result of their illness giving rise to problems with patient compliance with respect to oral administration of drugs.
It is therefore an object of the present invention to provide pyridyl cyanoguanidines in the form of prodrugs with an improved solubility profile which prodrugs may be included in pharmaceutical compositions suitable for parenteral administration, i.e. liquid compositions in which the prodrug is dissolved in sufficient amounts to be converted to therapeutically effective quantities of the active compound on administration of the composition.
Furthermore, it has been found that pyridyl cyanoguanidine prodrugs exhibit an improved gastrointestinal absorption on oral administration. Consequently, it is another object of the invention to provide oral formulations of pyridyl cyanoguanidines as prodrugs with improved bioavailability.
Accordingly, the present invention relates to a compound of the general formula I 
wherein
X1 and X2 independently represent a bond; a straight, branched and/or cyclic hydrocarbon diradical, optionally substituted with one or more hydroxy, halogen, nitro, amino, cyano, aminosulfonyl, alkylsulfonylamino, alkylcarbonyl, formyl, aminocarbonyl or alkylcarbonylamino; a heteroarylene or non-aromatic heterocyclic hydrocarbon diradical, all of which are optionally substituted with one or more straight, branched and/or cyclic non-aromatic hydrocarbon radical, hydroxyl, halogen, amino, nitro, cyano, aminosulfonyl, alkylsulfonylamino, alkylcarbonyl, formyl, aminocarbonyl or alkylcarbonylamino;
Y1 and Y2 independently represent a bond, an ether diradical (Rxe2x80x2xe2x80x94Oxe2x80x94Rxe2x80x3), an amine diradical (Rxe2x80x2xe2x80x94Nxe2x80x94Rxe2x80x3), O, S, S(O), S(O)2, C(O), NHxe2x80x94CO, COxe2x80x94NH, SO2xe2x80x94N(Rxe2x80x2), methylene or N(Rxe2x80x2)xe2x80x94SO2 wherein Rxe2x80x2 and Rxe2x80x3 independently represent straight or branched hydrocarbon diradicals containing up to 4 carbon atoms;
Y3 represents O, Oxe2x80x94C(O), C(O)xe2x80x94O, N(R8), R8 being hydrogen or C1-4alkyl
R1 represents hydrogen or straight, branched and/or cyclic alkyl, optionally substituted with phenyl; or an aromatic hydrocarbon radical;
R2 represents aryl, heteroaryl or a non-aromatic heterocyclic hydrocarbon radical, all of which are optionally substituted; tetrahydropyranyloxy, di-(C1-4 alkoxy)phosphinoyloxy or C1-4 alkoxycarbonylamino;
R3 represents hydrogen; a straight, branched and/or cyclic hydrocarbon radical, optionally substituted with one or more amino, hydroxy, carboxy, halogen, nitro, cyano, alkoxy, aminocarbonyl, C1-4alkoxycarbonyl, C1-4alkoxycarbonylamino, sulfo, hydroxysulfonyloxy, dihydroxyphosphinoyloxy, phosphono, sulfamino, aminosulfonyl, aminoacylamino or dialkoxyphosphinoyl; heteroaryl or a non-aromatic heterocyclic hydrocarbon radical, all of which are optionally substituted with one or more straight, branched and/or cyclic hydrocarbon radical, amino, hydroxy, carboxy, halogen, nitro, cyano, alkoxy, aminocarbonyl, C1-4alkoxycarbonyl, C1-4alkoxycarbonylamino, sulfo, hydroxysulfonyloxy, dihydroxyphosphinoyloxy, phosphono, sulfamino, aminosulfonyl, aminoacylamino or dialkoxyphosphinoyl; 
xe2x80x83wherein s is an integer from 1 to 200; R6 is hydrogen or an optionally substituted non-aromatic hydrocarbon radical; R7 is independently hydrogen or methyl;
R4 and R5 independently represent hydrogen; a straight, branched and/or cyclic hydrocarbon radical, optionally substituted with halogen, hydroxyl, halogen, amino, nitro or cyano;
A represents hydrogen, an optionally substituted, straight, branched and/or cyclic hydrocarbon radical, hydroxy, halogen, nitro, cyano, heteroaryl, heteroaralkyl or thiol;
m and r are independently integers from 0 to 4; and n is 0 or 1;
Zxe2x88x92 is a pharmaceutically acceptable anion, such as chloride, bromide, iodide, sulfate, methanesulfonate, p-toluenesulfonate, nitrate or phosphate.
Furthermore, the invention also relates to a compound of formula II, which is the free base form of the compounds of formula I, provided R4 is hydrogen 
wherein A, R1, R2, R3, R5, X1, X2, Y1, Y2, Y3, m, n and r are as indicated above.
It is understood that the compounds of the present invention include any tautomeric forms, optical isomers or diastereoisomers thereof. It is further understood that the invention includes pharmaceutically acceptable salts of compounds of formula I or II comprising basic or acidic groups.
On administration of a compound of formula I or formula II to a patient, the ester group R3xe2x80x94(CH2)rxe2x80x94(Y3)nxe2x80x94(CH2)mxe2x80x94COOCHR1xe2x80x94 is hydrolysed enzymatically to liberate the active compound of formula III 
wherein A, R2, R4, R5, X1, X2, Y1, and Y2 are as indicated above, together with the aldehyde R1CHO.
In the present context, the term xe2x80x9cprodrugxe2x80x9d is intended to indicate a derivative of an active compound which does not, or does not necessarily, exhibit the physiological activity of the active compound, but which may be subjected to enzymatic cleavage such as hydrolysis in vivo so as to release the active compound on administration of the prodrug. In this particular instance, the prodrug comprises the active compound which in itself is highly lipophilic provided with a side chain with predominantly hydrophilic properties imparting improved solubility characteristics to the prodrug, thereby making it more suitable for parenteral administration in the form of a solution or for oral administration to obtain an improved bioavailability. More specifically, the hydrophilic side chain selected for the compounds of the present invention comprises an ester group of formula R3xe2x80x94(CH2)rxe2x80x94(Y3)nxe2x80x94(CH2)mxe2x80x94COOCHR1xe2x80x94 (wherein R3, R1, Y3, m, n and r are as indicated above).
The term xe2x80x9calkylxe2x80x9d is intended to indicate a univalent radical derived from straight, branched or cyclic alkane by removing a hydrogen atom from any carbon atom. The term includes the subclasses primary, secondary and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, tert.-butyl, isopentyl, isohexyl, cyclohexyl, cyclopentyl and cyclopropyl.
The term xe2x80x9carylxe2x80x9d is intended to indicate radicals of carbocyclic aromatic rings, optionally fused bi-, tri- or tetra-cyclic rings wherein at least one ring is aromatic, e.g. phenyl, naphthyl, indanyl, indenyl, 1,4-dihydronaphtyl, flourenyl or tetralinyl.
The term xe2x80x9cheteroarylxe2x80x9d is intended to indicate radicals of heterocyclic aromatic rings, in particular 5- or 6-membered rings with 1-3 heteroatoms selected from O, S and N, or optionally fused bicyclic rings, of which at least one is aromatic, with 1-4 heteroatoms, e.g. pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridyl, pyrimidyl, purinyl, quinolinyl, chromenyl or carbazolyl.
The term xe2x80x9caralkylxe2x80x9d is intended to indicate an aromatic ring with an alkyl side chain, e.g. benzyl.
The term xe2x80x9chalogenxe2x80x9d is intended to indicate fluoro, chloro, bromo or iodo.
The term xe2x80x9caminosulfonylxe2x80x9d indicates a radical of the formula xe2x80x94S(O)2NRa2, wherein each Ra independently represents either hydrogen or alkyl.
The term xe2x80x9calkylsulfonylaminoxe2x80x9d indicates a radical of the formula xe2x80x94NRa2xe2x80x94S(O)2xe2x80x94Rb, wherein each Ra independently represents hydrogen or alkyl, and Rb represents alkyl.
The term xe2x80x9calkylcarbonylxe2x80x9d indicates a radical of the formula xe2x80x94C(O)Rb, wherein Rb is as just described.
The term xe2x80x9caminoxe2x80x9d indicates a radical of the formula xe2x80x94N(Ra)2, wherein each Ra independently represents hydrogen or alkyl.
The term xe2x80x9calkylcarbonylaminoxe2x80x9d indicates a radical of the formula xe2x80x94NRaC(O)Rb, wherein Ra and Rb are as just described.
The term xe2x80x9calkoxyxe2x80x9d indicates a radical of the formula ORb, wherein Rb is as just described.
The term xe2x80x9calkoxycarbonylxe2x80x9d is intended to indicate a radical of the formula xe2x80x94C(O)xe2x80x94ORb, wherein Rb is as indicated above.
The term xe2x80x9caminoacylaminoxe2x80x9d is intended to indicate a radical of the formula xe2x80x94NHxe2x80x94C(O)xe2x80x94Rcxe2x80x94NH2, wherein Rc is a diradical known from any natural amino acid, H2Nxe2x80x94Rcxe2x80x94COOH, or its enantiomer.
The term xe2x80x9caminocarbonylxe2x80x9d is intended to indicate a radical of the formula xe2x80x94C(O)xe2x80x94NRa2, wherein each Ra independently represent hydrogen or alkyl.
The term xe2x80x9calkoxycarbonylaminoxe2x80x9d is intended to indicate a radical of the formula xe2x80x94NRaxe2x80x94C(O)xe2x80x94ORb, wherein Ra and Rb are as indicated above.
The term xe2x80x9chydrocarbonxe2x80x9d is intended to indicate a compound comprising only hydrogen and carbon atoms, it may contain one or more double or triple carbon-carbon bonds, and it may comprise cyclic moieties in combination with branched or linear moieties. The term may be qualified as xe2x80x9cnon-aromatic heterocyclicxe2x80x9d, which is intended to indicate saturated or partly saturated cyclic compounds with 1-3 heteroatoms selected from O, S or N or optionally fused bicyclic rings with 1-4 heteroatoms, such as pyrrolidinyl, 3-pyrrolinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d is intended to indicate salts prepared by reacting a compound of formula I or II comprising a basic group with a suitable inorganic or organic acid, e.g. hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, acetic, phosphoric, lactic, maleic, phthalic, citric, propionic, benzoic, glutaric, gluconic, methanesulfonic, salicylic, succinic, tartaric, toluenesulfonic, sulfamic or fumaric acid. Pharmaceutically acceptable salts of compounds of formula II comprising an acidic group may be prepared by reaction with a suitable base such as sodium hydroxide, potassium hydroxide, ammonia or the like.
In a preferred embodiment of the invention, X1 and Y1 are both bonds, while X2 is a straight, branched or cyclic, saturated or unsaturated hydrocarbon diradical with 4 to 20 carbon atoms; Y2 is O, S, C(O) or methylene; R2 is optionally substituted aryl, heteroaryl, di-(C1-4alkoxy)phosphinoyloxy, C1-4alkoxycarbonylamino or tetrahydropyranyloxy; Y3 represents O or N(R8), wherein R8 is hydrogen or C1-4alkyl; R3 is hydrogen, straight or branched C1-6alkyl, C3-6cycloalkyl, C2-6alkenyl or C2-6alkynyl, all of which are optionally substituted with amino, carboxy, aminocarbonyl or C1-4alkoxycarbonyl; optionally substituted aryl, aralkyl, heteroaryl or 
wherein
s is an integer from 1 to 200;
R6 is hydrogen or C1-4alkyl;
R7 is hydrogen or methyl;
R1 is hydrogen, straight or branched C1-4alkyl, aralkyl or aryl;
A, R4 and R5 are all hydrogen;
m and n are independently 0 or 1; r is 0;
and Zxe2x88x92 is a pharmaceutically acceptable anion, such as chloride, bromide, iodide, sulfate, methanesulfonate, p-toluenesulfonate or nitrate.
In another embodiment of the compounds of formula I or II, m and n are 0, and R3 is straight or branched C1-6alkyl, optionally substituted with amino, hydroxy, carboxy, halogen, nitro, cyano, alkoxy, aminocarbonyl, C1-4alkoxycarbonyl, C1-4alkoxycarbonylamino, sulfo, hydroxysuIfonyloxy, dihydroxyphosphinoyloxy, phosphono, sulfamino, aminosulfonyl, aminoacylamino or dialkoxyphosphinoyl.
In still another embodiment of the compounds of formula I or II, n is 1, m is 0, Y3 is NR8, wherein R8 is as indicated above, and R3 is hydrogen; straight or branched C1-6alkyl, optionally substituted with amino, hydroxy, carboxy, halogen, nitro, cyano, alkoxy, aminocarbonyl, C1-4alkoxycarbonyl, C1-4alkoxycarbonylamino, sulfo, hydroxysulfonyloxy, dihydroxyphosphinoyloxy, phosphono, sulfamino, aminosulfonyl, aminoacylamino or dialkoxyphosphinoyl; or R3 and R8 together with the nitrogen atom of Y3 form a 5-, 6- or 7-membered ring.
In a still further embodiment of the compounds of formula I or II, n is 1, m is 0, Y3 is O, and R3 is straight or branched C1-6alkyl, optionally substituted with amino, hydroxy, carboxy, halogen, nitro, cyano, alkoxy, aminocarbonyl, C1-4alkoxycarbonyl, C1-4alkoxycarbonylamino, sulfo, hydroxysulfonyloxy, dihydroxyphosphinoyloxy, phosphono, sulfamino, aminosulfonyl, aminoacylamino or dialkoxyphosphinoyl.
In a still further embodiment of the compounds of formula I or II, n is 1, m is 0 or 1, Y3 is O, and R3 is R6xe2x80x94(Oxe2x80x94CH2xe2x80x94CH2)s, wherein s is an integer from 1 to 150, in particular from 1 to 120, preferably from 1 to 80, more preferably from 1 to 50, such as from 1-30, e.g. from 1 to 20, and R6 is hydrogen, methyl or ethyl. Particularly preferred in this embodiment, s is an integer from 2 to 10, such as 3, 4 or 5, and R6 is methyl.
In a further preferred embodiment of the compounds of formula I or II, n is 1, m is 0, Y3 is O, and R3 is a 5, 6 or 7 membered non-aromatic heterocyclic hydrocarbon radical. Particular preferred in this embodiment, R3 is pyrrolidinyl, piperidyl or hexahydro-1H-azepinyl.
In a preferred embodiment of the compounds of formula I or II, R2 is optionally substituted aryl, in particular phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, hydroxy, C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, nitro, cyano, amino, aminocarbonyl, sulfamoyl or C1-4hydroxyalkyl. A particular preferred substituent is halogen, such as chloro.
In a further preferred embodiment of the compounds of formula I or II, X1 is a bond and X2 is a C4-12 hydrocarbon diradical, or Y1 is a bond and Y2 is O.
Examples of specific compounds of formula I are
Compounds of formula I may be prepared by reacting a compound of formula III 
wherein A, R2, R4, R5, X1, X2, Y1 and Y2 are as indicated above, with a compound of formula IV 
wherein R1, R3, Y3, m, n and r are as indicated above, and B is a leaving group, such as Cl, Br or I. In addition R3 and Y3 may optionally contain protecting groups.
The reaction of a compound of formula III with a compound of formula IV may be performed in a solvent-free environment or in an inert solvent such as acetonitrile at a temperature between room temperature and 150xc2x0 C. to afford a compound of formula I optionally after removal of protecting groups.
The compounds of formula IV are known from the literature or may be prepared by methods well known to persons skilled in the art, e.g. by reacting a carboxylic halide of formula V
R3 xe2x80x94(CH2)rxe2x80x94(Y3)nxe2x80x94(CH2)mxe2x80x94C(xe2x95x90O)xe2x80x94Bxe2x80x83xe2x80x83V
wherein R3, Y3, B, m, n and r are as indicated in formula IV, with the proviso that m is different from 0 when n is 1, with an aldehyde of formula VI
R1xe2x80x94C(xe2x95x90O)xe2x80x94Hxe2x80x83xe2x80x83VI
wherein R1 is as indicated above, optionally in the presence of a catalyst such as anhydrous zinc chloride or anhydrous aluminium chloride.
When n is 1 and m is 0, compounds of formula IV may be prepared by reacting a compound of formula VII
R3xe2x80x94(CH2)rxe2x80x94Y3xe2x80x94Hxe2x80x83xe2x80x83VII
wherein R3, Y3 and r are as indicated in formula IV, with a compound of formula VIII 
wherein R1 and B are as indicated above.
The reaction between a compound of formula VII and a compound of formula VIII may be performed at a temperature between room temperature and xe2x80x9470xc2x0 C. in an inert organic solvent, such as dichloromethane, in the presence of a suitable base such as pyridine.
In another method compounds of formula IV in which B is chlorine are prepared by reacting a compound of formula IX
R3xe2x80x94(CH2)rxe2x80x94(Y3)nxe2x80x94(CH2)mxe2x80x94COOxe2x88x92M+xe2x80x83xe2x80x83IX
wherein R3, Y3, m, n and r are as indicated in formula V and M+ is suitable metal cation, e.g. an alkalimetal cation, or a tertiary ammonium ion, with a compound of formula X.
Xxe2x80x94CH(R1)xe2x80x94Clxe2x80x83xe2x80x83X
wherein R1 is as indicated above and X is iodo bromo or chlorosulfonyloxy.
The reaction between IX and X may be performed in a suitable solvent such as dimethylformamide at a suitable temperature, e.g. at room temperature, when X is iodo or bromo. When X is chlorosulfonyloxy the reaction may be performed under phase transfer conditions as described in Synthetic Communications 14, 857-864 (1984).
Compounds of formula IV in which B is chloro may be transformed into the corresponding compounds in which B is iodo by reaction with sodium iodide in acetone or acetonitrile.
The compounds of formulae V, VI, VII, VIII, IX and X are either known from the literature or may be prepared by methods well known to persons skilled in the art.
Compounds of formula III are known from the literature and may be prepared by any one of the methods disclosed in, for instance, EP 660 823, WO 98/54141, WO 98/54143, WO 98/54144, WO 98/54145, WO 00/61559 and WO 00/61561.
A compound of formula I, provided that R4 is hydrogen may be converted into the corresponding free base of formula II by treating a solution of a compound of formula I in an appropriate inert solvent, e.g. dichloromethane, with a suitable base, e.g. aqueous sodium bicarbonate. The free base of formula II may be reconverted into a salt of formula I by treating a solution of a compound of formula II in an appropriate inert solvent, e.g. dichloromethane, with a suitable acid of formula ZH, wherein Z is as indicated above.
In another aspect, the invention relates to pharmaceutical formulations of a compound of formula I or II intended for the treatment of proliferative diseases. The formulations of the present invention, both for veterinary and for human medical use, comprise active ingredients in association with a pharmaceutically acceptable carrier(s) and optionally other therapeutic ingredient(s). The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.
Conveniently, the active ingredient comprises from 0.1-100% by weight of the formulation. Conveniently, a dosage unit of a formulation contain between 0.07 mg and 1 g of a compound of formula I or II.
By the term xe2x80x9cdosage unitxe2x80x9d is meant a unitary, i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically and chemically stable unit dose comprising either the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers.
The formulations include e.g. those in a form suitable for oral (including sustained or timed release), rectal, parenteral (including subcutaneous, intraperitoneal, intramuscular, intraarticular and intravenous), transdermal, ophthalmic, topical, nasal or buccal administration.
The formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy, e.g. as disclosed in Remington, The Science and Practice of Pharmacy, 20th ed., 2000. All methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be in the form of discrete units, such as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid, such as ethanol or glycerol; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. Such oils may be edible oils, such as e.g. cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomers and polyvinylpyrrolidone. The active ingredients may also be administered in the form of a bolus, electuary or paste.
A tablet may be made by compressing or moulding the active ingredient optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient(s) in a free-flowing form such as a powder or granules, optionally mixed by a binder, such as e.g. lactose, glucose, starch, gelatine, acacia gum, tragacanth gum, sodium alginate, carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, waxes or the like; a lubricant such as e.g. sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride or the like; a disintegrating agent such as e.g. starch, methylcellulose, agar, bentonite, croscarmellose sodium, sodium starch glycollate, crospovidone or the like or a dispersing agent, such as polysorbate 80. Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered active ingredient and suitable carrier moistened with an inert liquid diluent.
Formulations for rectal administration may be may in the form of suppositories in which the compound of the present invention is admixed with low melting water soluble or insoluble solids such as cocoa butter, hydrogenated vegetable oils, polyethylene glycol or fatty acids esters of polyethylene glycols, while elixirs may be prepared using myristyl palmitate.
Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredients, which is preferably isotonic with the blood of the recipient, e.g. isotonic saline, isotonic glucose solution or buffer solution. The formulation may be conveniently sterilised by for instance filtration through a bacteria retaining filter, addition of sterilising agent to the formulation, irradiation of the formulation or heating of the formulation. Liposomal formulations as disclosed in e.g. Encyclopedia of Pharmaceutical Technology, vol.9, 1994, are also suitable for parenteral administration.
Alternatively, the compound of formula I may be presented as a sterile, solid preparation, e.g. a freeze-dried powder, which is readily dissolved in a sterile solvent immediately prior to use.
Transdermal formulations may be in the form of a plaster or a patch.
Formulations suitable ophthalmic administration may be in the form of a sterile aqueous preparation of the active ingredients, which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems e.g. as disclosed in Encyclopedia of Pharmaceutical Technology, vol.2, 1989, may also be used to present the active ingredient for ophthalmic administration.
Formulations suitable for topical or ophthalmic administration include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops.
Formulations suitable for nasal or buccal administration include powder, self-propelling and spray formulations, such as aerosols and atomisers.
In addition to the aforementioned ingredients, the formulations of a compound of formula I or II may include one or more additional ingredients such as diluents, buffers, flavouring agents, colourant, surface active agents, thickeners, preservatives, e.g. methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.
In the systemic treatment using the present invention daily doses of from 0.001-500 mg per kilogram body weight, preferably from 0.002-100 mg/kg of mammal body weight, for example 0.003-20 mg/kg or 0.003 to 5 mg/kg of a compound of formula I or II is administered, typically corresponding to a daily dose for an adult human of from 0.01 to 37000 mg. However, the present invention also provides compounds and compositions intended for administration with longer intervals, e.g. every week, every three weeks or every month. In the topical treatment of dermatological disorders, ointments, creams or lotions containing from 0.1-750 mg/g, and preferably from 0.1-500 mg/g, for example 0.1-200 mg/g of a compound of formula I or II is administered. For topical use in ophthalmology ointments, drops or gels containing from 0.1-750 mg/g, and preferably from 0.1-500 mg/g, for example 0.1-200 mg/g of a compound of formula I or II is administered. The oral compositions are formulated, preferably as tablets, capsules, or drops, containing from 0.07-1000 mg, preferably from 0.1-500 mg, of a compound of formula I or II per dosage unit.
In a preferred embodiment, the invention provides pharmaceutical compositions comprising a compound of formula I or II in combination with one or more other pharmacologically active compounds used in the treatment of proliferative diseases. Examples of compounds used in the treatment of proliferative diseases which may be used together with compounds of the present invention include S-triazine derivatives such as altretamine; enzymes such as asparaginase; antibiotic agents such as bleomycin, dactinomycin, daunorubicin, doxorubicin, idarubicin, mitomycin, epirubicin and plicamycin; alkylating agents such as busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, procarbazine and thiotepa; antimetabolites such as cladribine, cytarabine, floxuridine, fludarabine, fluorouracil, hydroxyurea, mercaptopurine, methotrexate, gemcitabin, pentostatin and thioguanine; antimitotic agents such as etoposide, paclitaxel, teniposide, vinblastine, vinorelbin and vincristine; hormonal agents, e.g. aromatase inhibitors such as aminoglutethimide, corticosteroids, such as dexamethasone and prednisone, and luteinizing hormone releasing hormone (LH-RH); antiestrogens such as tamoxifen, formestan and letrozol; antiandrogens such as flutamide; biological response modifiers, e.g. lymphokines such as aldesleukin and other interleukines; interferon such as interferon-xcex1; growth factors such as erythropoietin, filgrastim and sagramostim; differentiating agents such as vitamin D derivatives and all-trans retinoic acid; immunoregulators such as levamisole; and monoclonal antibodies, tumour necrosis factor xcex1 and angiogenesis inhibitors. Finally, ionising radiation, although not readily defined as a compound, is heavily depended on in the treatment of neoplastic diseases, and may be combined with the compounds of the present invention. Due to the severe side effects often experienced by patients receiving anti-neoplastic treatment it is often desirable also to administer therapeutica which are not themselves anti-neoplastic, but rather help relieving the side effects. Such compounds include amifostin, leucovorin and mesna.
In particular, anti-neoplastic compounds, such as paclitaxel, fluorouracil, etoposide, cyclophospamide, cisplatin, carboplatin, vincristine, gemcitabine, vinorelbine, chlorambucil, doxorubicin and melphalan appear beneficial in the combination compositions of the present invention.
It is envisaged that the combination composition of the present invention may be provided as mixtures of the compounds or as individual compounds intended for simultaneous or sequential administration. It lies within the capabilities of a skilled physician or veterinarian to decide time intervals in a sequential administration regime.
In a further aspect, the invention relates to a method of treating or ameliorating proliferative diseases or conditions, the method comprising administering, to a patient in need thereof, a pharmaceutical composition comprising a compound of formula I or II, which compound is hydrolysed enzymatically upon administration to provide a compound of formula III, in an amount sufficient to effect treatment or amelioration of said proliferative disease or condition, optionally together with another anti-neoplastic compound and/or ionising radiation.
In particular, proliferative diseases or conditions to be treated by the present method include a variety of cancers and neoplastic diseases or conditions including leukaemia, acute myeloide leukaemia, chronic myeloide leukaemia, chronic lymphatic leukaemia, myelodysplasia, multiple myeloma, Hodgkin""s disease or non-Hodgkin""s lymphoma, small or non-small cell lung carcinoma, gastric, intestinal or colorectal cancer, prostate, ovarian or breast cancer, head, brain or neck cancer, cancer in the urinary tract, kidney or bladder cancer, malignant melanoma, liver cancer, uterine or pancreatic cancer.
The invention also relates to the use of compounds of formula I or II, optionally together with other anti-neoplastic compounds, as indicated above, in the manufacture of medicaments. In particular, said medicament is intended to be used for the treatment of proliferative diseases, e.g. cancers as mentioned above.
As indicated above, it is preferred to administer the compounds of the invention parenterally, such as in a liquid, preferably aqueous, solution intended for intravenous injection or infusion. A suitable dosage of the compound of the invention will depend, inter alia, on the age and condition of the patient, the severity of the disease to be treated and other factors well known to the practising physician. The compound may be administered either orally or parenterally according to different dosing schedules, e.g. daily or with weekly intervals. In general a single dose will be in the range from 0.1 to 400 mg/kg bodyweight. Parenterally, the compound may be administered as a bolus (i.e. the entire dose is administered at once) or in divided doses two or more times a day or preferably as an intravenous infusion.